This application represents a renewal application for a Specialized Program of Research Excellence (SPORE) in Prostate Cancer from the Prostate Cancer Program of Dana-Farber/Harvard Cancer Center (DF/HCC). The DF/HCC Prostate Cancer SPORE has been continuously funded since 2002. DF/HCC is comprised of the following institutions: Dana-Farber Cancer Institute; Harvard Medical School; Harvard School of Public Health; Beth Israel-Deaconess Medical Center; Brigham and Women's Hospital; Massachusetts General Hospital; and Children's Hospital of Boston. In addition to the institutions in the DF/HCC, the Broad Institute is a collaborating institution in this grant. The DF/HCC Prostate Cancer SPORE has its administrative base at the DFCI. Dr. Philip Kantoff, who has led the DF/HCC Prostate Cancer Program and SPORE since their inception, is joined by Co-Directors Dr. William Hahn, a laboratory scientist at DFCI, and Dr. Steven Balk, a laboratory scientist at BIDMC. Dr. Kantoff reports directly to Dr. Edward Benz, Director of DF/HCC and President of DFCI. The DF/HCC Prostate Cancer SPORE has a broad and deep talent base and there is extensive institutional commitment. We take advantage of a large patient population and cutting edge technologies that are available to us as part of DF/HCC. We propose 5 Projects which address critical problems in prostate cancer and have translational components including 1) understanding the mechanism by which obesity impacts prostate cancer mortality 2) dissecting the clinical heterogeneity of Gleason 7 prostate cancer 3) elucidating the importance of the EZH2 signaling pathway 4) understanding the role that genomic change has on resistance to androgen deprivation therapy and on aggressive prostate cancer and finally 5) understanding the mechanism that underlie resistance to secondary forms of hormonal therapy. The five projects are supported by three Cores, an Administrative, a Biostatistics and Computional Biology and a Tissue and Pathology Core. We also have a highly successful Career Development Progam that selects talented phycian scientists and mentors them to independence and a Developmental Projects Program that generates new ideas for the SPORE in the future.